University of Groningen
Haematological response and overall survival in two consecutive Dutch patient cohorts with
AL amyloidosis diagnosed between 2008 and 2016
Rutten, Karlijn H G; Raymakers, Reinier A P; Hazenberg, Bouke P C; Nienhuis, Hans L A;
Vellenga, Edo; Minnema, Monique C
Published in: Amyloid DOI:
10.1080/13506129.2018.1536043
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Rutten, K. H. G., Raymakers, R. A. P., Hazenberg, B. P. C., Nienhuis, H. L. A., Vellenga, E., & Minnema, M. C. (2018). Haematological response and overall survival in two consecutive Dutch patient cohorts with AL amyloidosis diagnosed between 2008 and 2016. Amyloid, 25(4), 227-233.
https://doi.org/10.1080/13506129.2018.1536043
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Amyloid
The Journal of Protein Folding Disorders
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Haematological response and overall survival in
two consecutive Dutch patient cohorts with AL
amyloidosis diagnosed between 2008 and 2016
Karlijn H. G. Rutten, Reinier A. P. Raymakers, Bouke P. C. Hazenberg, Hans L.
A. Nienhuis, Edo Vellenga & Monique C. Minnema
To cite this article: Karlijn H. G. Rutten, Reinier A. P. Raymakers, Bouke P. C. Hazenberg, Hans L. A. Nienhuis, Edo Vellenga & Monique C. Minnema (2018): Haematological response and overall survival in two consecutive Dutch patient cohorts with AL amyloidosis diagnosed between 2008 and 2016, Amyloid, DOI: 10.1080/13506129.2018.1536043
To link to this article: https://doi.org/10.1080/13506129.2018.1536043
© 2018 Informa UK Limited, trading as Taylor & Francis Group
Published online: 04 Dec 2018.
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ORIGINAL ARTICLE
Haematological response and overall survival in two consecutive Dutch patient
cohorts with AL amyloidosis diagnosed between 2008 and 2016
Karlijn H. G. Ruttena , Reinier A. P. Raymakersa, Bouke P. C. Hazenbergb , Hans L. A. Nienhuisb, Edo Vellengac and Monique C. Minnemaa
a
Department of Haematology, Utrecht University, University Medical Centre Utrecht, Utrecht, The Netherlands;bDepartment of Rheumatology & Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; c
Department of Haematology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
ABSTRACT
Background: Although survival has improved in recent decades, the short-term prognosis of patients with immunoglobulin light chain (AL) amyloidosis remains grim. We aimed to assess overall survival (OS) of AL amyloidosis patients by comparing cohorts in two consecutive time periods.
Methods: Data were collected and compared on 126 patients from two tertiary referral centres in The Netherlands during the time periods 2008–2012 and 2013–2016.
Results: There was a non-significant trend to improved 6-month OS in the last cohort (78% vs. 67%, p ¼ .216, crude odds ratio 1.66, 95%CI 0.74–3.70, adjusted odds ratio 2.22, 95%CI 0.88–5.56). Patients in this cohort had higher Mayo risk scores (stage III 40% vs. 24%,p < .001 and revised stage IV 14% vs. 11%,p < .001), higher use of bortezomib (50% vs. 30%), and better haematological response (com-plete response/very good partial response in 39% vs. 27%, p < .001). Diagnostic delay was similar in both time periods.
Conclusions: In the 2013–2016 cohort there was a trend toward improved 6-month OS, and an improved haematological response. Patients in this cohort had more advanced cardiac disease and received bortezomib more frequently, but diagnostic delay was similar to the 2008–2012 cohort. For further prognostic improvement, practitioners should be more alert, especially for cardiac amyloidosis. Abbreviations: AL: amyloid light chain; ASCT: autologous stem cell transplantation; BMPC: bone mar-row plasma cells; BNP: B-type natriuretic peptide; CR: complete response; dFLC: difference between involved and uninvolved free light chains; FLC: free light chains; HDM: high dose melphalan; IMiD’s: immunomodulatory imide drugs; NT-proBNP: N-terminal proBNP; OS: overall survival; PR: partial response; SD: stable disease; UMC: University Medical Centre; VGPR: very good partial response
ARTICLE HISTORY Received 11 March 2018 Revised 26 September 2018 Accepted 10 October 2018 KEYWORDS AL amyloidosis; survival; prognosis; time trend
Introduction
Systemic immunoglobulin light chain (AL) amyloidosis is char-acterized by aggregation and deposition of monoclonal immunoglobulin free light chains (FLC) in several tissues, lead-ing to organ dysfunction. Clinical manifestations and outcomes depend on the extent of organ involvement. Cardiac involve-ment in particular has a major negative impact on prognosis. Another negative prognostic factor is a delay between start of symptoms and the diagnosis, because these patients present with more advanced organ damage [1–3].
The short-term prognosis of AL amyloidosis depends greatly on the extent of cardiac involvement. Biomarkers of heart failure and cardiac injury, such as B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) and troponins T or I are therefore used for risk assessment and monitoring. The long-term prognosis of patients with AL amyloidosis depends on haematological response after treat-ment and on overall organ involvetreat-ment. The latter is related
to the on-going supply of involved FLCs to the tissues. Consequently, serum FLCs, and especially the difference between the involved and uninvolved FLC (dFLC), can also be used for risk assessment and monitoring [4–6].
Therapy used for the treatment of multiple myeloma has been shown to be effective in AL amyloidosis as well [7]. New developments in treatment modalities for multiple myeloma have also changed treatment of the far less common AL amyl-oidosis [8]. The introduction of high dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) led to a better haematological response and organ response in AL amyloidosis patients [9]. Over the years, the treatment-related mortality of this procedure has declined, likely due to better patient selection [10]. However, most patients are not eligible for ASCT. Recently, proteasome inhibitors such as bortezomib and immunomodulatory imide drugs (IMiD’s) such as thal-idomide and lenalthal-idomide have become available [7,11]. A recently published study conducted in the Mayo Clinic CONTACTM. C. Minnema M.C.Minnema@umcutrecht.nl University Medical Centre Utrecht, Utrecht University, B02.226, Heidelberglaan 100, Utrecht, GA 3508, The Netherlands
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AMYLOID
showed that the introduction of melphalan-dexamethasone and bortezomib-based therapy as first-line therapy has con-tributed to improved overall survival (OS). This study, which included 1551 patients, showed an improvement of the short-term prognosis: 6 month OS increased from 63% in cohort 2000–2004 to 76% in cohort 2010–2014 (p < .001). Nevertheless, short-term mortality remained high [11].
Until the 1980s, survival of patients with AL amyloidosis in the Netherlands was very poor, with a median OS of 7 months. This was primarily because the vast majority of patients had been left untreated [12]. This improved to a median OS of 12 months in patients diagnosed between 1990 and 2003, who were treated with prednisone and mel-phalan or HDM followed by ASCT [13]. However, more recent outcomes of patients with systemic AL amyloidosis in the Netherlands are unknown. We therefore evaluated 126 AL amyloidosis patients who were diagnosed between 2008 and 2016 in two tertiary referral centres for amyloid-osis in the Netherlands, and compared the last cohort (2013–2016) with the first cohort (2008–2012).
Methods Patients
We retrieved information on 186 patients who were diag-nosed with systemic AL amyloidosis at the University Medical Centre Utrecht (UMC Utrecht) and the University Medical Centre Groningen (UMC Groningen). At the UMC Groningen the registry started in 2008 and at the UMC Utrecht in 2012. Patients were eligible for inclusion if diag-nosed with systemic AL amyloidosis and treated at either centre between January 1 2008 and December 31 2016. Of the 186 patients, 48 patients were not eligible because they fell outside the scope of our study: seven patients were diag-nosed in an earlier time period; in five patients the diagno-sis of amyloidodiagno-sis was uncertain; 35 patients were seen for a second opinion and were treated elsewhere; and one patient who received stem cell therapy was sent back immediately afterwards to the referring hospital. Of the remaining 138 eligible patients with AL amyloidosis, 12 (8.7%) were lost to follow-up, thus leaving 126 patients for analysis. We divided these patients into two cohorts based on the year of diagno-sis; 2008–2012 (cohort I) including 46 patients, and period 2013–2016 (cohort II) including 80 patients.
In all included cases, amyloidosis was diagnosed by positive Congo red staining of tissue retrieved using a screening fat tis-sue aspirate or targeted organ biopsy. Systemic involvement was confirmed by another biopsy from a different organ or tis-sue, or by the combination of clinical features typical for amyl-oidosis in an organ or tissue other than that from which a biopsy with a positive Congo red stain was obtained. Amyloid type AL was preferably demonstrated by a positive anti-kappa or anti-lambda light chain staining using immunohistochemis-try in combination with a definitely negative staining for amyl-oid type amylamyl-oid A (AA) and amylamyl-oid transthyretin (ATTR). In addition, increased production of either kappa or lambda FLC had to be present. Diagnostic delay was defined as the time between the first documented signs or symptoms of AL
amyloidosis and the date that amyloid had been diagnosed by biopsy. Both organ involvement and haematological response were based on consensus criteria [6,14]. Haematological response categories are complete response (CR), very good par-tial response (VGPR), parpar-tial response (PR), stable disease (SD) and progression. At UMC Utrecht, the cardiac biomarkers BNP and troponin I were measured, while at UMC Groningen, NT-proBNP and troponin T were used. Based on these cardiac biomarkers, both the Mayo 2004 and 2012 staging system crite-ria were applied [4,5]. For bone marrow plasma cell percentage, the highest estimated percentage was used. Treatment was cate-gorized as ASCT after high-dose or intermediate-dose melpha-lan, melphalan-dexamethasone (MDex), bortezomib-based regimen, IMiD-based regimen, single-agent dexamethasone or “other treatment”. The latter category included treatment com-monly used for Waldenstr€om’s macroglobulinemia: rituximab monotherapy or rituximab in combination with chlorambucil or dexamethasone and cyclophosphamide.
Data analysis
Thev2 test was used to compare differences between nom-inal and ordnom-inal variables, and the one-sample t-test and the independent-samples t-test were used to compare means between groups. Kaplan–Meier analysis was used for survival analysis. Besides our own data, in the analysis we used historical data on overall survival of systemic amyloidosis previously reported in The Netherlands [12,13]. Only patients with AL amyloidosis were included in the analysis. OS was calculated using time from diagno-sis to last follow-up or death. Due to the short follow-up in the most recent cohort, median OS was not expected to be reached. In addition we determined 6-month OS and 2-year OS. The 6-month follow-up was available for all patients, but the 2-year follow-up only for 25% of patients. The majority of these missing data points were from the 2013-2016 cohort, because the 2 year follow-up of part of this cohort has not yet taken place. To compare the 6-month OS of the two cohorts (2008–2012 vs. 2013–2016), we used a multivariate analysis in line with a previous study [11], with adjustment for age, gender and variables related to severity of disease (dFLC, number of bone mar-row plasma cells (BMPC), number of organs involved and heart involvement). To deal with missing values (six for dFLC and 14 for BMPC) we did multiple imputation (5 times) before multivariate analysis and used pooled esti-mated adjusted odds ratios with 95% confidence intervals. Because data from UMC Utrecht was only available from 2012 onwards, we performed sensitivity analysis compar-ing the results from UMC Utrecht and UMC Groncompar-ingen selectively from 2012 to 2016. Analyses were performed with SPSS version 23.
Results
Baseline characteristics
The baseline characteristics are shown in Table 1. The mean age at diagnosis was 64 years (range 45–82) and 57% of the 2 K. H. G. RUTTEN ET AL.
patients were male. The mean time from start of complaints to diagnosis was 14.7 months (range 0–156 months). This delay did not decrease as the study progressed and was 14.0 months in cohort I versus 14.9 in cohort II (p ¼ .947). The most common symptoms at diagnosis were oedema (43.7%), dyspnoea (42.9%), fatigue (38.9%), weight loss (33.3%), peripheral sensory neuropathy (27.0%), changed defaecation pattern (22.2%), orthostatic hypotension (19.8%) and bleeding tendency (15.1%). Four patients did not have any complaints at diagnosis. The percentage of patients with two or more organs involved did not differ between the two cohorts and was 49% in cohort II and 39% in cohort I (p ¼ .491). Cardiac involvement was seen in 74% of patients in both cohorts.
Lambda restricted light chains were found in 71% of the patients and in 4 patients (5%) the light chain amyloidosis was associated with Waldenstr€om’s disease. The median dFLC was significantly higher in cohort II (16.9 mg/dL in cohort I and 18.2 mg/dL in cohort II, p ¼ .008). There was no significant difference in mean BMPC percentage between the cohorts (15% in cohort I and 12.5% in cohort II,p ¼ .107).
The cardiac biomarkers NT-proBNP, BNP, troponin I and T were not always available in the data. As a result,
only 75% of the patients were staged by the Mayo 2004 staging system [4] and 63% by the revised Mayo 2012 stag-ing system [5]. More patients had poorer prognoses in cohort II; 40% of patients from cohort II were in Mayo stage III compared to 24% from cohort I (p < .001), while 14% from cohort II were in revised Mayo stage IV com-pared to 11% from cohort I (p < .001). Based on only highly elevated NT-proBNP of >8500 ng/L, 13 patients in cohort I and 14 patients in cohort II (p ¼ .055) were classified as very high-risk patients.
Treatment
In total, 109 patients (87%) were treated. The other 13% of the patients did not receive treatment due to advanced dis-ease or death before start of treatment. Patients received up to five lines of treatment with a median of one line. In total, 48 different combinations of regimens were used as first-line therapy and were grouped into five categories, which are shown in Table 2. In the first line of treatment, the use of bortezomib-based therapy increased from 30% in cohort I to 50% in cohort II, whereas the use of IMiD-based ther-apy decreased from 30% to 8%.
Table 1. Baseline characteristics of 126 AL amyloidosis patients, divided into two consecutive time periods.
Characteristic Both time periods (n ¼ 126) Period 2008–2012 (n ¼ 46) Period 2013–2016 (n ¼ 80) p value
Mean age in years 63.9 64.1 63.8 .469
Age 65 years, n (%) 60 (48) 22 (48) 38 (48) .972 Male, n (%) 72 (57) 27 (59) 45 (56) .789 Organs involved,n (%) >2 organs 57 (45) 18 (39) 39 (49) .296 Neurological 46 (37) 15 (33) 31 (39) .491 Heart 93 (74) 34 (74) 59 (74) .984 Liver 26 (21) 6 (13) 20 (25) .061 Renal 78 (62) 27 (59) 51 (64) .813 Gastro-intestinal tract 33 (26) 12 (26) 21 (26) .984 Lung 6 (5) 3 (7) 3 (4) .482 Soft tissue 33 (26) 13 (28) 20 (25) .689 Light chains k restricted, n (%) 90 (71) 33 (72) 57 (71) .747 Unknown 1 0 1 Median dFLC in mg/dL 17.5 16.9 18.2 .008 Unknown 6 0 6 dFLC<0.5 mg/dL, n (%) 3 (2) 0 (0) 3 (4) .062 dFLC 18 mg/dL, n (%) 59 (49) 22 (48) 37 (46) .159 Mean BMPC in % 13.5 15.0 12.5 .107 Unknown 14 1 13
Brain natriuretic peptides
Unknown 8 2 6 Median NT-proBNP in ng/L 2100.5 2462.0 2100.5 .402 NT-proBNP 332 ng/L, n (%) 84 (82) 35 (46) 49 (61) .079 NT-proBNP 1800 ng/L, n (%) 54 (53) 21 (46) 33 (41) .071 BNP median, pg/mL 745 487.0 1139.0 .236 BNP 100 pg/mL, n (%) 23 (88) 4 (9) 19 (24) .036 Troponins Unknown 19 4 15 Troponin I median, ng/L 0.04 0.00 0.05 .306 Troponin I 0,10 lg/L, n (%) 7 (29) 0 (0) 7 (9) .045 Troponin T median,lg/L 0.032 0.00 0.048 .665 Troponin T 0,035 lg/L, n (%) 38 (46) 11 (24) 27 (34) <.001 Troponin T 0.025 lg/L, n (%) 46 (55) 13 (28) 33 (41) <.001
Mayo AL amyloidosis 2004 stage, %
I/II/III/unknown 11/29/34/25 15/50/24/11 9/18/40/34 <.001
Mayo AL amyloidosis 2012 stage, %
I/II/III/IV/unknown 14/14/22/13/37 24/24/24/11/17 9/9/21/14/48 .002
dFLC: difference between the involved and uninvolved free light chains; BMPC: bone marrow plasma cells; BNP: B-type natriuretic peptides; NT-proBNP: N-terminal proBNP. Ap-value < 0.05 is considered bold significant.
Overall, 25 patients (20%) received ASCT as first line of treatment in both cohorts. In 23 out of 25 patients, ASCT was preceded by induction therapy. In cohort I, ASCT was preceded by IMiD-based induction therapy in 50% of the
patients and by bortezomib-based induction therapy in 30% of the patients. In cohort II, IMiD-based induction therapy was used in 23% of patients and bortezomib-based induc-tion therapy in 75%.
Haematological response
The haematological response to first line of treatment improved between the cohorts; CR/VGPR was reached in 27% in cohort I and 39% in cohort II (p < .001). In patients who received ASCT, the percentage of patients who achieved VGPR or CR was similar in both cohorts: 70% in cohort I and 65% in cohort II (p ¼ .521). Haematological response data to first line of treatment was missing for 24% of patients in cohort I and 28% in cohort II.
Survival
OS in our study was compared to survival in previous stud-ies reported in The Netherlands (Figure 1(A)). The median OS significantly improved over time: from 7 months in patients diagnosed between 1964–1985 to 12 months in patients diagnosed between 1990–2003 and to 53.5 months in patients in our study who were diagnosed between 2008–2016 (p < .001) [12,13].
The median OS was 52.5 months for cohort I and 53.5 months for cohort II (p ¼ .503). The 6-month OS was 67% for cohort I and 78% for cohort II (OR 1.66 (95% CI 0.74–3.70), p ¼ .216) and the 2-year OS was 60% for cohort I and 66% for cohort II (p ¼ .349). Survival by cohort is shown in Figure 1(B). This OS curve suggests trend (non-significant) towards improved survival in the most recent cohort. The multivariate analysis for factors influencing 6-month survival is shown in Table 3. After adjustment for number of organs involved, heart involvement, dFLC and BMPCs, the trend to improved survival remained, with a higher point estimate (OR 2.22, 95% CI 0.88–5.56, p ¼ .09).
Median OS was much higher in patients without cardiac involvement (median OS was not reached in patients without cardiac involvement compared to 42.1 months for patients with cardiac involvement, p ¼ .005). This was also seen in the 6-Figure 1. Survival from time of diagnosis per cohort. (A)Survival of historical
cohorts 1964–1985 12 and 1990–2003 13 versus complete current study cohort 2008–2016, p < .001. (B) Survival of cohort 2008–2012 versus cohort 2013–2016, p ¼ .503.
Table 2. Treatment and haematological response of 126 AL amyloidosis patients, divided into two consecutive time periods.
Characteristic Both time periods (n ¼ 126) Time period 2008–2012 (n ¼ 46) Time period 2013–2016 (n ¼ 80) p value First line of treatment,n (%)
ASCT 25 (20) 9 (20) 16 (20) .045 MDex 3 (2) 1 (2) 2 (3) Bortezomib-based 54 (43) 14 (30) 40 (50) IMiD-based 20 (16) 14 (30) 6 (8) - Lenalidomide 8 (6) 2 (4) 6 (8) - Thalidomide 12 (10) 11 (24) 1 (1) Single-agent dexamethasone 2 (2) 0 (0) 2 (3) Others 5 (4) 2 (4) 2 (3) No treatment 17 (13) 6 (13) 11 (14)
Haematological response to first line treatment (n5 110) (%)
Complete response 24 (22) 8 (20) 16 (23) <.001 .563
Very good partial response 14 (13) 3 (7) 11 (16)
Partial response 22 (20) 9 (22) 13 (19) –
Stable disease 17 (15) 8 (20) 9 (13)
Progression 4 (4) 3 (7) 1 (1)
Unknown 29 (26) 10 (24) 19 (28)
ASCT: autologous stem cell transplantation; MDex: melphalan dexamethasone; IMiD: immunomodulatory imide drugs. 4 K. H. G. RUTTEN ET AL.
month OS (94% without cardiac involvement compared to 66% with cardiac involvement, p ¼ .004) and the 2-year OS (87% compared to 56%, p ¼ .002). The survival curve of patients with and without cardiac involvement in both cohorts is shown in Figure 2(A). A trend to improved survival was seen in patients presenting with fewer than two organs involved (median OS of 56.8 months with fewer than 2 organs involved compared to 39.0 months with 2 or more organs involved, p ¼ .075); 6-month OS, 81% compared to 66%, p ¼ .047; 2-year OS, 73% compared to 54%, p ¼ .028). The median OS was higher in patients with dFLC<18 mg/dL than in patients with dFLC18 mg/dL (median OS was not reached in patients with dFLC<18 mg/dL compared to a median OS of 11.47 months in patients with dFLC>18 mg/dL, p ¼ .002), 6-month OS 82% compared to 64% (p ¼ .03) and 2-year OS 78% compared to 49% (p < .001). The survival curve of patients according to dFLC cut-off 18 mg/dL is shown in Figure 2(B). The Mayo 2004 and 2012 staging systems were both prognostic for OS. The 6-month OS for patients with Mayo 2004 risk score I was 100%, with II it was 78% and with III it was 53% (p < .001); the 2-year OS for patients with these risk scores was 92%, 73% and 38% (p < .001), respectively. The 6-month OS for patients with Mayo 2012 risk score I was 94%, with II it was 89%, with III it was 57% and with IV it was 38%. The 2-year OS for patients with these risk scores was 89%, 82%, 49% and 31% (p ¼ .002), respectively. The OS was also dependent on the type of therapy patients received (p < .001). In patients who received ASCT as the first line of treatment, 6-month OS was 100% and 2-year OS was 91%. For patients who received non-ASCT therapy, the median OS was 52.9 months, the 6-month OS was 75% and the 2-year OS was 67%. For the 13% of patients who did not receive any treatment, the median OS was 2.4 months, the 6-month OS was 29% and the 2-year OS was 10%.
Sensitivity analysis comparing results of the UMC Utrecht and the UMC Groningen
The 6-month OS was 83% (25/30) at UMC Utrecht and 69% (45/65) at UMC Groningen. The 2-year OS was 67% (20/30) at UMC Utrecht and 63% (41/65) at UMC Groningen. A CR or VGPR in this time period was reached in 59.1% of the patients at UMC Utrecht and 47.2% at UMC Groningen (p ¼ .38). Differences between the two centres in OS and haematological response were not significant.
Discussion
In this retrospective analysis of 126 AL amyloidosis patients diagnosed and treated in the two expertise centres in The Netherlands, we evaluated presentation, diagnostic delay, treatment and outcome between 2008 and 2016 and com-pared two patients cohorts (2008–2012 and 2013–2016).
The time between symptom onset and diagnosis was similar in the two cohorts, with a median diagnostic delay of 15 months. This is similar to the results of a recent patient survey, with a delay in diagnosis of more than one year in 37.1% of the patients [15]. This median delay in diagnosis is longer than previously reported. The Mayo Clinic reported a delay of 10 months, an Italian study reported 6 months, and a Chinese study reported 7 months [11,16,17]. Early diagnosis is crucial; it enables early treat-ment intervention and may therefore prevent irreversible organ damage and improve the prognosis [16]. Lousada et al. stated that only 7.6% of the patients received the diag-nosis of amyloidosis after visiting one physician, and that 31.8% visited 5 physicians before receiving the diagnosis [15]. This suggests that the diagnosis of AL amyloidosis should be considered more often by cardiologists, nephrolo-gists, neurologists and haemato-oncologists. Although initia-tives were undertaken in the Netherlands to improve awareness among both lay people and physicians to reduce diagnostic delay, such as the launch of a patient organiza-tion in 2013 and the initiaorganiza-tion of expert centres in 2015, these efforts have not yet resulted in greater awareness and earlier diagnosis. Therefore, improving the awareness of medical specialists should still have high priority.
The total rate of cardiac involvement was similar in both cohorts (74%), and was in line with other cohort studies that reported rates between 53 and 76% [11,17,18]. Surprisingly, patients in the more recent cohort had even more advanced cardiac disease with higher Mayo 2004 and 2012 risk scores. Moreover, in the more recent cohort a higher (but not significantly higher) proportion of the patients presented with two or more organs involved. Also, the median dFLC was significantly higher in the more recent cohort (18.2 mg/dL versus 16.9 mg/dL). This dFLC value is another important prognostic factor, and is lower than that reported in a study from the Mayo Clinic: a dFLC of 23.7 mg/dL [11].
It should be noted that our study was based on patients referred to tertiary centres. Compared to other studies, Table 3. Two models with adjusted odds ratios (OR) for 6-month overall survival in 126 AL amyloidosis patients.
Model 1 Adjusted OR (95% CI) p value Model 2 Adjusted OR (95% CI) p value
Cohort 2013-2016 2.17 (0.85–5.56) .106 2.22 (0.88–5.56) .091
Heart involvement 0.16 (0.03–0.78) .023 0.17 (0.04–0.81) .026
2 organs involved 0.42 (0.17–1.08) .069 0.43 (0.17–1.09) .074
BMPC 10% 0.99 (0.97–1.00) .102 0.99 (0.97–1.00) .100
dFLC per mg/dL 1.00 (0.99–1.00) .100 1.00 (0.99–1.00) .133
Age per year 0.97 (0.92–1.02) .256 – –
Female gender 0.74 (0.29–1.85) .512 – –
95% CI: 95% confidence interval; OR: odds ratio.
Cohort 2013–2016 was compared to cohort 2008–2012. The unadjusted or crude odds ratio was 1.66 (95% CI 0.74–3.70). When adjusted for age, gender and variables related to severity of disease mentioned inTable 3, the odds ratio increased to 2.17 (95% CI 0.85–5.56) and when adjusted only for variables related to severity of disease, the odds ratio further increased to 2.22 (95% CI 0.88–5.56).
patients with more advanced disease may therefore be over-represented. In a 2012 Swedish nationwide registration study, the estimated incidence of AL amyloidosis was 3.2 per million inhabitants [19]. In The Netherlands, compris-ing 17 million inhabitants, 55 newly-diagnosed patients with AL amyloidosis per year would then be expected. In two of our expertise centres, 186 patients were seen during 9 years,
or about 20 new patients per year on average. We therefore analyzed approximately 40% of all cases of AL amyloidosis in the Netherlands that were diagnosed from 2008 to 2016.
A factor that could have affected our study concerns the new treatment options that have become available in recent decades. In our study population, 13% of the patients did not receive any treatment due to advanced disease or death before start of treatment. This is a higher percentage than previously reported in a study by the Mayo Clinic, in which 6%, 7% and 11% of the patients remained untreated in the time periods 2000–2004, 2005–2009 and 2010–2014 respectively [11]. In our study and others reported in literature, in recent time periods patients received bortezomib-based therapy more often as first line treatment in the more recent time periods [11] and in recent years induction therapy changed from
IMiD-based therapy to bortezomib-based therapy.
Importantly, these new treatment options led to significantly improved haematological response in our study. In patients who received first line treatment, the CR/VGPR rate was 27% in the 2008–2012 cohort and 39% in the 2013–2016 cohort. In a retrospective study at the Mayo Clinic, a much higher CR/VGPR rate was reported (51% in 2000–2004, 58% in 2005–2009 and 66% in 2010–2014). This could be partly explained by the higher ASCT rate in this selected Mayo cohort, which was about one-third compared to 20% in our cohort. In the Mayo cohort, patients who received ASCT had the highest response rate (65% to 70%) and this figure remained stable during the time period studied [11]. As reported by D’Souza et al., not only haematological response after ASCT improved over the years, but early mortality after ASCT also declined between 1995 and 2012 [20].
In our analyses, a non-significant trend to improved 6-month OS was seen in the more recent cohort (67% in the 2008–2012 cohort and 78% in the 2013–2016 cohort). The point estimate of this trend was even better after adjustment for variables related to severity of disease (dFLC, BMPCs, number of organs involved and heart involvement) (crude OR 1.66, 95% CI 0.74–3.70, adjusted OR 2.22, 95% CI 0.88–5.56). This effect is very likely the result of more effective treatment over the years, even though patients in the more recent cohort have more severe disease (higher Mayo risk scores and dFLC). In line with our results, study at the Mayo Clinic showed a statistically significant improvement in 6-month OS from 63% in the 2000–2004 cohort to 76% in the 2010–2014 cohort [11].
Strengths and limitations
We analyzed treatment data for approximately 40% of the total AL amyloidosis population in The Netherlands, that was diagnosed between 2008 and 2016.
Limitations: In our study, 8.7% of patietns were lost to follow up and we had missing values in some determinants and in haematological response as shown inTable I. If miss-ing values in haematological response data occured for dif-ferent reasons in one cohort compared to the other and/or were not completely random, this could bias the results by either overestimating or underestimating the effect. Both of Figure 2.Survival of subgroups in all 126 AL amyloidosis patients. (A) Cardiac
involvement versus no cardiac involvement in cohort I and II, p < .025. (B) Difference between the involved and uninvolved free light chain<18 mg/dL or >18 mg/dL in cohort I and II, p ¼ .003.
the above shortcomings are related to the use of routine care data. Another limitation concerns patient follow-up. Although all patients had 6 months of follow up, a majority (75%) had not yet completed two years of follow-up. Data on 2-year OS should therefore be interpreted cautiously. Finally, limitations are the retrospective nature of the study and the relatively low number of outcomes.
Conclusion
By comparing the 2008–2012 and 2013–2016 cohorts we showed an improvement in haematological response of AL amyloidosis patients within the last decade. There was also a trend towards improved 6-month OS. These favourable findings are probably the result of improvements in anti plasma cell treatment over the years. However, the delay in diagnosis is still too high and patients in the most recent cohort even presented with more advanced disease and worse risk scores. To reduce the long diagnostic delay that currently blocks further improvement in survival, awareness of amyloidosis should be improved among cardiologists, nephrologists, neurologists and other medical specialists. Acknowledgements
Karlijn H.G. Rutten is a medical student who participates in the Honours programme of the Faculty of Medicine of the University Medical Centre Utrecht, The Netherlands.
Disclosure statement
The authors report no conflicts of interest.
ORCID
Karlijn H. G. Rutten http://orcid.org/0000-0002-7691-2802 Bouke P. C. Hazenberg http://orcid.org/0000-0003-1827-0482 Edo Vellenga http://orcid.org/0000-0002-7741-8697
Monique C. Minnema http://orcid.org/0000-0002-3139-8379
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